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Dr. Lorne Brandes Tel: (204) 787-2139 Fax: 787-2190
Lab: 789-3675 |
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Research Interests: My research has concentrated on the role of histamine and other bioamines as intracellular regulators of cell growth and homeostasis. In collaboration with Prof. Frank LaBella in the Department of Pharmacology, I have demonstrated that histamine binds intracellularly to sites in microsomes, nuclei and chromatin. A major proportion of the microsomal histamine sites represents P450 enzymes. Employing spectral analysis, we have demonstrated that histamine binds directly to the heme iron of P450. We have also identified many endogenous and exogenous antagonists of histamine binding to P450, including polyamines, H1-antihistamines, phenothiazines, tricyclic antidepressants, antiestrogens and antiandrogens. Through binding to substrate sites in the heme cavity or, in the case of polyamines, to sites external to the heme cavity, these agents allosterically inhibit histamine binding to the heme iron. We have shown a strong correlation among (a) in vitro drug potencies to inhibit (i) histamine binding to P450, (ii) P450-mediated demethylation and aminopyrine, and (iii) mitogenesis, and (b) in vivo potencies to modulate tumor growth. We have proposed that intracellular histamine governs the catalytic activity of P450 enzymes that metabolize lipid mediators involved in growth regulation, including hormones and prostanoids. Antagonism of the histamine/P450 complex by various endogenous substances or exogenous drugs may perturb steady-state levels of these monooxygenase-generated mediators of proliferation. The discovery of intracellular histamine binding sites followed the synthesis, in my laboratory, of N,N-diethyl-2-[4-(phenylmethyl) phenoxy] ethanamine.HCl (DPPE). DPPE, which is structurally similar to various arylalkykamines of the classes noted above, has both antiproliferative and cytotoxic properties. DPPE is cytoprotective to normal bone marrow and gut endothelial cells but potentiates cytotoxicity of a variety of antineoplastic agents to malignant cells in vitro and in vivo. DPPE has been licensed to Bristol-Meyers Squibb and is currently in phase 2 and 3 clinical trials in breast and prostate cancer. Recent Publications:
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